Hereditary Early-Onset Parkinson's Disease Caused by Mutations in <i>PINK1</i>
Enza Maria Valente, Patrick M. Abou‐Sleiman, Viviana Caputo, Miratul M. K. Muqit, Kirsten Harvey, Suzana Gispert, Zeeshan Ali, Domenico Del Turco, Anna Rita Bentivoglio, Daniel G. Healy, Alberto Albanese, Robert Nussbaum, Rafael González-Maldonado, Thomas Deller, Sergio Salvi, Pietro Cortelli, William P. Gilks, David S. Latchman, Robert J. Harvey, Bruno Dallapiccola, Georg Auburger, Nicholas Wood
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.